Hydrogels have long been of interest for biological and biomaterial applications due to their high water content that mimics the interstitial tissue environment, ensures high diffusive permeability, and provides biomimetic mechanical strengths. Particular interest has been given to PEG hydrogels and poly(2-hydroxyethyl methacrylate) (pHEMA) hydrogels because, in addition to the general properties of hydrogels, they are also commonly considered be low fouling, bioinert, and versatile.
pHEMA hydrogels have found use in and been studied for applications such as contact lenses, artificial cornea, drug delivery vehicles, cartilage substitutes, and tissue scaffolds, among others. The hydration of pHEMA, however, is lower than that of native tissue, and its fouling, while low, is higher than other nonfouling materials. Furthermore, pHEMA functionalization via the hydroxyl group is generally difficult.
PEG hydrogels are routinely used, and can only be modified for applications that require a bioinert background with specific added bioactive functionalities for controlled in vitro and in vivo uses when additional functional groups are introduced into PEG hydrogels. However, it has been found that PEG is subject to oxidation. The susceptibility of PEG to oxidative damage reduces its utility for applications that require long-term material stability. For applications in which maximal biological stability and nonfouling are required, however, PEG-based materials are insufficient.
Recently, zwitterionic compounds, including poly(carboxybetaine methacrylate) (pCBMA, Scheme 1, structure 1), have been demonstrated to be ultra-low-fouling, meaning that surfaces coated with these polymers allow less than 5 ng/cm2 protein adsorption. It was also demonstrated that surfaces coated with zwitterionic poly(carboxybetaine methacrylate) greatly resist non-specific protein adsorption, even from undiluted blood plasma and serum and also prohibit long-term bacterial colonization by Pseudomonas aeruginosa for up to 10 days at room temperature. The ultra-low-fouling of zwitterionic materials is due to high hydration around the opposing charges and the high energetics required to remove that hydration layer. Furthermore, CBMA (carboxybetaine methacrylate) is functionalizable through conventional EDC/NHS chemistry.
Because of the high hydration and ultralow fouling properties of zwitterionic materials, zwitterionic hydrogels are of interest as hydrogels with superior suitability for biomedical applications. Low protein adhesion on sulfobetaine methacrylate (SBMA) and mixed charge hydrogels, and low cell adhesion on carboxybetaine methacrylate gels, have been demonstrated. The zwitterionic hydrogels studied so far, however, have shown low mechanical strength, which limits their potential biological uses. A need therefore exists for hydrogels having improved mechanical properties.
Another fundamentally limiting feature of these zwitterionic hydrogels is the dearth of hydrophilic crosslinkers. The most commonly used of the commercially available “hydrophilic” crosslinker is N,N′-methylenebis(acrylamide) (MBAA, Scheme 1, structure 2). Water-soluble at very low concentrations, this crosslinker is only moderately soluble at crosslinker concentrations around 10%, especially in the salt solutions that are ideal for zwitterionic hydrogel formation. Additionally problematic for polymerization with pSBMA and pCBMA is the inherent incompatibility of the polymerizable moieties: the greatly different chemical structure of the crosslinker may result in poor incorporation into the growing methacrylate polymer chains. Perhaps the most unacceptable feature of MBAA as a crosslinker in zwitterionic hydrogels is that it does not structure water the way the zwitterionic monomers do. Structured water around the opposing charges in a zwitterionic material provides the nonfouling mechanism; MBAA will disrupt the ordered water and present locations where proteins, bacteria, and even cells, may bind and foul the hydrogel. Furthermore, the MBAA crosslinker is not functionalizable.
A need exists for crosslinked zwitterionic hydrogels that retain the advantageous properties of non-crosslinked zwitterionic hydrogels. The present invention seeks to fulfill this need and provides further related advantages.